The recent resurgence of vector-borne diseases, most notably malaria, dengue hemorrhagic fever, amongst other devastating infections, driven by resistance to conventional containment and treatment tactics, requires the unceasing search for novel ways of controlling both vectors and pathogens. Along with goal-oriented research, exploratory basic studies of vectors and their interactions with pathogens and vertebrate hosts must remain an integral part of these efforts if we are to maintain the upper hand in the battle against vector-borne disease in the future. The present grant proposal aims to elucidate the molecular mechanisms underlying one of the most critical processes in the life history of the mosquito: the specific recognition of yolk protein precursors by oocyte receptors leading to their accumulation as the protein reserve necessary for successful egg and embryo development. This proposed research rests on the accomplishments of the previous five-year grant, during which important progress has been achieved in the understanding of the oocyte receptor (VgR) for the major yolk protein precursor, vitellogenin (Vg): VgR has been purified, its properties characterized, and its cDNA cloned. The availability of the VgR cDNA provides an unparalleled opportunity to address in this proposal the question of the molecular basis of VgR-ligand recognition. This will be achieved through direct testing of the ligand binding properties of mutagenized and expressed VgR variants. To aid mutant design, structural computer-modeling and analysis of VgR will be utilized. In addition, I propose to study the receptor for vitellogenic carboxypeptidase (VCP), another important mosquito yolk protein precursor. Finally, based on the acquired information concerning yolk protein precursor-receptor interaction, the development of receptor- mediated targeted gene transfer to mosquito oocytes will be initiated. Accomplishment of these goals will significantly advance our understanding of mosquito egg development and will likely suggest applications of this knowledge in novel vector control strategies.